19-nor-7alpha-methyl or 19-nor-20-spirox-4,14-dien-3-one and 18-methyl derivatives thereof

ABSTRACT

THE COMPOUNDS, 19-NOR-7A-METHYL, 18-HYDROGEN OR METHYL-20-SPIROX-4.14-DIEN-3-ONE AND THE CORRESPONDING 19--NOR-SPIRO-LACTONES ARE PROVIDED, PREPARED FROM THE CORRESPONGING 19-NOR-3-OXO-SPIROX-4, 14-DIENES. THE COMPOUNDS ARE USEFUL AS ORALLY-EFFECTIVE ANTIESTROGEENS AND ARE ALSO ANABOLIC AGENTS HAVING LOW ANDROGENICITY.

3,787,394 Patented Jan. 22, 1974 19-NOR-7a-METHYL OR 19 NOR-20-SPIROX-4,14-

DlEN-S-ONE AND 18-METHYL DERIVATIVES THEREOF Glen E. Arth, Cranford, and Gary H. Rasmusson,

Watchung, N.J., assignors to Merck & Co., Inc., Rahway, NJ.

No Drawing. Continuation-impart of abandoned application Ser. No. 67,615, Aug. 27, 1970. This application Oct. 4, 1972, Ser. No. 295,090

Int. Cl. C07c 173/00 US. Cl. 260-23955 R 7 Claims ABSTRACT OF THE DISCLOSURE The compounds, 19-nor-7u-methyl, 18-hydrogen or methyl-20-spirox-4,14-dien-3-one and the corresponding 19-nor-spiro-lactones are provided, prepared from the corresponding 19-nor-3-oxo-spiroX-4,l4-dienes. The compounds are useful as orally-effective antiestrogens and are also anabolic agents having low androgenicity.

SUMMARY OF THE INVENTION This application is a continuation-in-part application of US. Ser. No. 67,615 filed Aug. 27, 1970, now abandoned.

The compounds of the present invention are 19-nor-7amethyl, l8-hydrogen or methyl-ZO-spirox-4-en-3-ones and the corresponding spirolactones which possess a high anabolic/ androgenic ratio. This high anabolic/ androgenic ratio is surprising, in light of the prior art teachings of other compounds in the series. In addition, the compounds possess a potent antiestrogen effect and are orally active as antiestrogens or as anabolic compounds. This latter high oral activity in the spiroxene series has heretofore been relatively low. The specific utility of these compounds is to antagonize the uterine growth stimulating activity of estrone and compounds of estrone-like activity. A further use is as anabolic compounds in animals and humans.

The compounds of this invention can be represented by the following formula;

in which R is R' is CH and R" is CH or C H preferred group of compounds are those in which R is -CH-,, R is CH and R" is CH or C H An even more preferred compound is .thatin which R is CH R" is CH and R is CH Another preferred compound is that in which R is and R is CH These compounds can be prepared using the following reaction synthesis, diagrammed in Flow Sheet I.

FLOW SHEET I cmo omo ---R' CHQO. RI

cmo cmo --R' no RI! "CH3OH=CH3 cmo qmo II R -----0H. H.cH.on

ciao" v o 1 GHsO CHaO The reaction scheme starts from the known 3methylether l7-ketals of estrone or 7a-methyl estrone, Compound A. When R" in Compound A is ethyl, the starting materials can be easily prepared using preparations and procedures available in the literature. An example is given supra of this preparation. The chosen Compound A is first brominated at position 16 using pyridinium bromide perbromide. In general, the bromination reaction takes place in an inert organic solvent at low temperatures (O- 25 C.). The estrone ether and the penbromide are employed in approximately equimolar amounts.

In the next step of the reaction, the 16-bromo derivative (B) is dehydrobrominated to the A Compound C. This dehydrobromination reaction is elfected by refluxing in a high boiling solvent (i.e., about 120-200 C.) in the presence of an alkali metal alkoxide, e.g., potassium-tbutoxide. The mixture is refluxed for several hours, cooled, and the product extracted with an aromatic hydrocarbon. After evaporation and recrystallization, the product C is recovered.

In the third step, the 17,17-ethylene dioxy group of C is transformed to the 17-keto derivative D, by means of dilute acid, such as p-toluene sulfonic acid, in an aqueousorganic solvent mixture. The oragnic sol-vent is preferably acetone. The product D is recovered after concentration and filtration.

Compound D is then converted to the 17-acetoxy-l,3,5 (l),1 4,l6-pentaene derivative E by treatment with ptoluene sulfonic acid and acetic anhydride. .The pentaene E is then reduced to the tetraene-17-ol, Compound F. The reduction conditions utilize sodium borohydride in aqueous alcohol, preferably methanol or ethanol. Excess hydride is neutralized by the addition of acid such as glacial acetic acid. The product (F) is "recovered by the concentration of organic solvent'extracts.

The alcohol group at 17 of Compound F is then selectively oxidized to the l7-keto derivative (G). A suitable oxidation system is a dipyridine-chromium VI complex in a solvent such as methylene chloride. The oxidation proceeds rapidly at room temperature.

Compound G is then treated with allyl magnesium chloride in ether to yield the 17B-hydroxy-17a-a1lyl, Compound -H. The reaction proceeds within 1-2 hours or less at room temperature. The 17a-allyl substituent is transformed to the 17a-(3'-hydroxypropyl)-175-hydroxy, Compound I. An excess of diborane in an organic solvent (suitably tetrahydrofuran) in the presence of 2-methyl-2- butene is first employed at low temperatures (-20 to 0 C.). The reaction mixture is then made basic, suitable with NaOI-I; then hydrogen peroxide is added and the mixture allowed to stand 8-12 hours at room temperature. The product, Compound I, is a key intermediate. By reference to the Flow Sheet, it can be seen that it can be treated following at least two separate processes to yield the desired A -spiroxenone (Compound I).

. The first process of reaction, Compound I, is a threestep procedure via Compounds K and M. The first step, yielding Compound K, is a Birch reduction using metallic lithium and t-butanol in a solvent mixture of liquid ammonia and diethyl ether. After refluxing for 3-4 hours, the product K is separated and suspended in alcohol. The suspension is acidified with HCl and stirred at room temperature. After about 20-24 hours, the mixture is neutralized and the product, Compound M, recovered. The final step is the ring closure of the spiroxa ring using ptoluene sulfonyl chloride or methane sulfonyl chloride in pyridine. When the lactone is desired, a ring closing oxidizing agent, e.g., chromic acid in acetone, is used.

Alternatively, Compound Q can first be converted to the spiroxene by closing the l7p-hydroxy-17a-(3-hydroxypropyl) substituents using p-toluene sulfonyl chloride in pyridine or chromic acid in acetone, followed by the Birch reduction and acid-catalyzed hydrolysis or ring closing oxidizing agent to yield the final desired A spiroxenone, Compound I.

Although the above reaction sequence is illustrated using the 3-methoxy ether of the starting compound, other loweralkoxy compounds could be used with equal success. Loweralkoxy is used to mean all alkoxy groups having l-6 carbon atoms.

The 7a-methyl-spiroxene compounds of the invention having a high anabolic/ androgenic ratio are useful when it is desired to increase body weight and build muscle tissue Without stimulating an androgenic response.

It will be apparent to one skilled in the art that the 18CH compounds prepared by total synthesis are d,lisomeric mixtures. The d-isorner can be separated by the usual isolation techniques; alternatively, it can be prepared from d-isomeric intermediate compounds described in the literature.

The invention is further illustrated by means of the following examples, but it is not to be considered as limited thereto.

PREPARATIVE EXAMPLE 19-nor-7u-methyl-20-spirox- 4, l4-dien-18-methyl-3 -one The starting material for this example is I9-nor-7umethyl l8 methyl pregna-4-en-l7B-ol-3-one, which is described in J. Med. Chem. 9, 782 (1966). The processes are all as usually used and known to those skilled in the art. In addition, the final product is described in Great Britain Pat. 1,143,437 (1969). The analogous starting material for the 7a-non-substituted compound is also disclosed in J. Med. Chem. 9, 782 (1966 and is employed in these same reactions, in the same fashion.

STEP A 0H OAc s a. H .1 W

HI 0 HIGH;

" J. Med. Chem. 9, 782 (1966).

7 EXAMPLE 3 3-methoxy-7a-methyl-estra-1,3,5 10) ,15-tetraene-17-one A solution of 10 g. (0.031 mole) of the ketal prepared in Example 2 and 500 mg. of p-toluene sulfonic acid hydrate in a mixture of 750 ml. of acetone and 125 ml. of water is stirred at room temperature for 105 minutes. It is then treated with 800 mg. of sodium bicarbonate. After concentration of the mixture under reduced pressure to about one-half of its original volume it is diluted with one liter of saturated sodium chloride solution. The separated product is isolated by filtration, washed well With water and then dried. Recrystallization from 900 ml. of heptane yields 3 methoxy-h-methyl-estra-1,3,5-(10),15-tetraene- 17-one.

EXAMPLE 4 17-acetoxy-3-methoxy-7a-methyl-estra1,3,5 10),l4,16- pentaene To a solution of 690 mg. (2.44 mmoles) of the enone prepared in Example 3 in 20 ml. of acetic anhydride is added 120 mg. of p-toluene sulfonic acid. The mixture is stirred at room temperature overnight and then concentrated under reduced pressure (100 mm.) at 90 to about one-third of its original volume. The remaining anhydride is removed by treatment with a saturated solution of sodium bicarbonate. The product is extracted into diethyl ether and worked up to give a crystalline, colored residue. Recrystallization from methanol gives the product, 17 acetoxy 3 methoxy 7a-methyl-estra- 1,3,5 10) ,l4,16-pentaene.

EXAMPLE 5 3 -me thoxy-7a-me thyl-e stra- 1, 3,5 1 14-tetraene-1 713-01 To a solution of 1.367 g. (4.2 mmoles) of the enol acetate prepared in Example 4 in 75 ml. of ethanol is added at 0 a solution of 825 mg. of sodium borohydride in 75 m1. of ethanol-water (10:3). The mixture is kept at -10 for 16 hours and then at room temperature for 4 hours. Glacial acetic acid is added to neutralize the excess hydride and the resulting mixture concentrated to near dryness under reduced pressure. The residue is extracted with ethylacetate and' the resulting extract is washed, dried and concentrated to give a glass which crystallized on trituration with alcohol. Recrystallization from isopropanol yields the product, 3-methoxy-7mmethyl-estra-1,3,5(),14-tetraen-17fl-ol.

EXAMPLE 6 3-methoxy-7a-methyl-estra-l,3,5(10), l4-tetraen-17-one A solution of 9.3 g. (0.0328 mole) of 3-methoxy-7umethyl-estra-l,3,5 (10),14-tetraen-17;3-ol prepared as in Example 5 in 300 ml. of methylene chloride is added at a rapid dropwise rate to a stirred suspension of 46.5 g. (0.18 mole) of dipyridine-chromium (VI) complex in 800 ml. of methylene chloride at room temperature. The mixture is stirred 45 minutes and then filtered. The residue is washed with ethyl acetate and the organic layers are combined. Water is added to the filtrates and suflicient ethyl acetate is added to make the organic layer less dense than water. After the organic layer is washed with water, it is dried over sodium sulfate and concentrated to leave -10 g. of crystalline residue. Recrystallization from methanol gives the desired 3-methoxy-7a-methyl-estra- 1,3,5(10),14-tetraen-17-one.

EXAMPLE 7 3-methoxy-7a-methyl-estra-1,3,5 10 14-tetraen-17aallyl-17/8-ol 5.3 g. of the steroid prepared in Example 6 is dissolved in 268 ml. of diethyl ether and cooled to 0 C. 150 ml. of 3 M allylmagnesium chloride in tetrahydrofuran is added and the mixture stirred at room temperature for one hour. The solution is quenched with ammonium chloride and extracted with ethyl acetate, then washed with water. After drying and evaporating, a yellow oil is obtained. Recrystallization from methanol yields a white crystalline solid, 3-methoxy-7a-methyl-estra-1,3,5(10),14- tetraen-17a-allyl-175-01.

EXAMPLE 8 3 -methoxy-7a-methyl-estra-1,3,5(10), 14-tetraen-17a- 3'-hydroxypropyl)-l7;8-ol

A dry flask under N atmosphere is prepared for reaction by adding 14 ml. of 1 M diborane (20% excess) in 14 ml. distilled tetrahydrofuran. The vessel and contents are cooled to 20 C. and 5 ml. of 2-methyl-2 butene in 5 m1. of tetrahydrofuran is added and stirred for /2 hour. The temperature is maintained at 20 C. To the flask is added 4.0 g. of the allylic alcohol steroid prepared in Example 7 in 20 ml. of tetrahydrofuran. The flask is stirred at 0 C. for two hours. After cooling to 20 C., 14 ml. of 3 N NaOH is added slowly. The reaction mixture foams and when foaming ceases, 14 ml. of 30% aqueous H 0 is added. The mixture is allowed to stand overnight at room temperature. The reaction is quenched by dilution with water and the tetrahydrofuran is evaporated under vacuum. The residue is crystallized, filtered, and purified. The product, 3-methoxy-7u-methylestra-1,3,5 (10),14-tetraen-17a-(3-hydroxypropyl)-17 3-01 is recovered and used in the next step without further identification.

EXAMPLE 9 3-methoxy-7a-methyI-estra-Z,5(10),14-trien-17u-(3"-hydroxypropyl)-17p3-ol To a dry flask equipped with a Dry Ice condenser and magnetic stirrer device under a N atmosphere is added 0.5 g. of the steroid (prepared in Example 8) suspended in 7 ml. of t-butanol and 7 ml. of diethyl ether. 20 ml. of anhydrous liquid ammonia is added to the flask. Suflicient solid lithium wire is then added to turn the solution dark blue. The mixture is refluxed for 3-4 hours. Methanol is added to quench the reaction and the ammonia allowed to evaporate overnight under the N stream. At this point, 25 ml. of water and 25 ml. of diethyl ether is added to the reaction flask. The mixture is extracted with methylene chloride, washed with water, dried and evaporated. A white crystalline powder is recrystallized from methanol and identified as 3-methoxy-7a-methyl-estra-2,5(10),l4- trien-17u-(3-hydroxypropyl)-175-01.

EXAMPLE 10 7a-methyl-estra-4, 14-dienl7oz- 3 '-hydroxypropyl) 17B- ol-3-one EXAMPLE 11 7a-methyl-19 nor-20-spiroxa-4, l4-dien-3-one 820 mg. of the diol prepared in Example 10 is dissolved in 8 cc. of pyridine and cooled to 0 C. To this solution is added 820 mg. of p-toluene sulfonyl chloride and the mixture stirred at room temperature overnight. The solu tion is diluted slowly with water and an oily substance separates. This oil, after extraction with ethyl acetate and washing with water, is dried and evaporated to yield a dark oil. The oil is purified by thin layer chromatography on a silica gel with a 2% methanol/chloroform eluant. The product is taken up in benzene and recrystallized from a 10% ethanol/benzene mixture to give the product, 70;- methyl-19-nor-20-spiroxa-4,14-dien-3-one.

A l% solution of the I'Z-hydroxy steroid in 1:1 acetic anhydride:pyridine when allowed to stand 18 hours at 25 gives the corresponding 17-acetate, on concentration to dryness and crystallization from aqueous methanol- A 5% solution of the steroid in a mixture of 5:1 methanol:trimethylorthoformate is treated at 0 with 2,4-dinitrobenzene sulfonic acid (0.1 weight of steroid). After minutes at 0 an excess of pyridine is added and the product enol ether is isolated after addition of water.

STEP C HOQJHI The enol ether (5% in acetone) is treated sequentially at 0 with one equivalent of sodium acetate (5% in Water), one equivalent of N-bromosuccinimide and a slight excess of glacial acetic acid. The mixture is then stirred 2 hours at 0 and treated with aqueous potassium iodide solution. The product is extracted into ether, washed with sodium thiosulfate solution, then water and finally dried over sodium sulfate. The solution is concentrated and the residue dissolved in acetone (-10% The solution is then treated at with concentrated hydrochloric acid. After .40 minutes at 35, the mixture is allowed to stand at room temperature for 3 hours. The mixture, partially concentrated, is treated with water and extracted with ethyl acetate. The organic layer gives a dark residue whichis chromatographed on alumina to afiord the desired sterol 17-acetate.

STEP D CHaO 0A0 OH CHaO HI 110 HI H:

6 STEP E K CHMDM CHsO VIHCH:

A 5% solution of the steroid in acetone is treated with 8 N chromic acid solution until the red color of the oxidant persists for one minute. Water is added and the mixture partially concentrated. The product is worked up in ether to give the desired ketone which can be recrystallized from aqueous methanol.

STEP F 0 H V f r onto morn CHsO mon,

A mixture comprised of the steroid, ethylene glycol toluene-sulfonic acid and benzene (ratio 12110.1:25) is refluxed with water separation for 8 hours. The solution is cooled and treated with excess sodium bicarbonate solution. The organic layer is washed with water and then saturated sodium chloride. After drying and concentration, the ketal is isolated as a crystalline solid.

EXAMPLE 1 16-brom0-17,17-ethylenedioxy-3-methoxy-7 x-methylestra-1,3,5(10)-triene To a solution of 34 g. (0.104 mole) of the l7-ethylene ketal of 7u-methyl estrone methyl ether in 1100 ml. of tetrahydrofuran is added with stirring at 0, 35.5 g. (0.11 mole) of pyridinium bromide perbromide in portions over five minutes. The mixture is stirred at 0 for one hour, the orange bromine color being replaced by yellow. The insoluble material is removed by filtration and the filtrate is concentrated to about ml. It is then added to an excess of 5% sodium bicarbonate solution with stirring. The separated product is isolated by filtration and washed well with water. After drying under reduced pressure, the solid is recrystallized from ethyl acetate, and identified as l6-bromo-17,17-ethylenedioxy-3-methoxy-7a-methyl-estra-1,3,5 10) -triene.

EXAMPLE 2 l7, 17-ethylenedioxy-3 -methoxy-7 a-methyl-estra- 1,3,5 10) ,1 S-tetraene A suspension of 113 g. of freshly prepared potassium t-butoxide in 1500 ml. of xylene is heated until 250 ml. of the solvent is removed. The bromoketal prepared in Example 1 (32.3 g., 0.079 mole) is added and the mixture refluxed under nitrogen for 18 hours. After cooling to room temperature 500 g. of ice is added to the reaction mixture. The phases are separated and the aqueous phase 9 EXAMPLE 12 3methoxy-19-nor-20-spiroxa-7a-methyl-1,3,5 10) ,14- tetraene 800 mg. of the diol prepared in Example 8 is dissolved in 8 cc. of pyridine and cooled to C. To this solution is added 800 mg. of p-toluene sulfonyl chloride and the mixture stirred at room temperature overnight. The solution is then diluted with water. The crude product is recovered as an oil, which after purification and recrystallization, is identified as 3-methoxy-19-nor-20-spiroxa-7amethyl- 1,3,5( l4-tetraene.

EXAMPLE 13 7 a-methyl- 19-nor-20-spiroxa-4, 14-dien-3 -one The product prepared in Example 12 is treated with anhydrous ammonia and solid lithium in t-butanol following the procedure of Example 9. The product obtained is 19-nor-20-spiroxa-4-methoxy-7a-methyl-2,5 (10) ,14-triene. This latter product is then treated with acid following the procedure of Example 10 to yield the 7u-methyl-l9-nor- 20-spiroxa-4,14-dien-3-one final product.

EXAMPLE 14 7u-methyl-19-nor-20-spiroxa-4, 14-dien-3 ,21-dione EXAMPLE 15 19-nor-20-spiroxa-4,14-dien-3-one; l9-nor-20-spiroxa- 4,14-dien-3,21-dione These compounds are prepared using the processes of Examples 1-15 above. The starting material is the 17- ethylene ketal of estrone-3-methyl ether. Following the sequential treatment, the products 19-nor-20-spiroxa-4,14- dien-3-one and 19-nor-20-spiroxa-4,14-dien-3,21-dione are isolated and identified.

What is claimed is:

1. The process of preparing a compound having the following structure:

RI! lo 10 wherein R" is loweralkyl, 'R" is methyl or ethyl, and R is hydrogen or methyl, which comprises (a) reducing, using sodium borohydride in aqueous alcohol, a compound having the following structure n I0 I to yield the corresponding 1,3,5 (10),14-tetraen-17- hydroxy compound, and (b) selectively oxidizing the 17-OH group to the desired final product. 2. A compound having the formula wherein R is either 0 -CH2 or -1 R is either H or CH and R" is methyl or ethyl.

3. The compound of claim 2 wherein R is OH 4. The compound of claim 3 which is O- CH:

R" being either methyl or ethyl.

5. The compound of claim 2 wherein R" is ethyl.

6. The compound of claim 5 which is a mixture of d,loptically active isomers.

7. The d-stereoisomer of the compound of claim 5.

References Cited UNITED STATES PATENTS 3,254,074 5/1970 Arth et a1 260-23955 HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,787,394 Da d January 22, 1974 Inirentofls) GLEN E. ARTH & GARY H. RASMUSSON It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In Claim 2, the structure should read as follows:

. Signed and sealed this 1L 1:h day of May 19714..

SEAL) A Attest:

EDWARD M .F LLTGHER, JR Attesting Officer C. MARSHALL DANN Commie:sioner of Patents 

